The ability to specifically enhance the level of expression of human tumor antigens may be an important advantage in overcoming the limitations associated with antigenic heterogeneity in immunodiagnostic and/or immunotherapeutic clinical protocols. We have reported that human interferons (IFNs), particularly interferon-gamma (IFN-gamma), can enhance the level of expression of TAG-72 and CEA, two distinct human tumor antigens, on the surface of human carcinoma cells. In particular, experimental studies clearly showed that the increase in CEA expression by a variety of human colon carcinoma cells was accompanied by higher levels of CEA-related mRNA transcripts following IFN-gamma treatment. Those studies provided the initial insights into the mechanism(s) involved in CEA regulation by that biological response modifier. Some human colon carcinoma cells were unresponsive to the ability of IFN to augment the level of tumor as well as normal (HLA) antigen expression. IFN treatment of those cells, however, successfully increased 2', 5'A synthetase indicating the presence of a viable IFN receptor. CEA expression was enhanced in those same cells treated with a chloride-substituted analogue of cyclic AMP, B-Cl-cAMP. Those results indicate the presence of a cAMP-dependent protein kinase pathway through which 8-Cl-cAMP can increase CEA expression. In another study, a potentially novel tumor antigen, immunologically related to CEA and strongly upregulated by IFN-gamma, was identified in 6 of 8 human gastric carcinoma cells. Molecular cloning of this 110,000 Mr antigen will address its relationship with that of the large CEA gene family as well as the possible role which the IFNs play in its regulation. Serum samples were collected from a variety of clinical trials that investigated the therapeutic efficacy of different IFNs on a variety of human carcinomas. Analysis of the samples taken before, during and after IFN treatment revealed an increase in serum TAG-72 and CEA levels in approximately 65% of the patients. This occurred in patients whose sera were TAG-72 and/or CEA-positive before IFN therapy, and was not, by and large, observed in sera from patients diagnosed with noncarcinoma malignancies. The findings indicate the ability of therapeutic doses of human IFNs to initiate biological effects at the tumor cell resulting, in this case, an increase in the amount of human tumor antigen secreted into the blood. Clinical trials are being planned to determine whether one could exploit this action in a diagnostic setting.